Acyl-CoA: cholesterol acyltransferase (ACAT) is an intracellular enzyme found in several different sites in the body, including the intestinal tract and the liver, which catalyzes the esterification of fatty acid and cholesterol to form cholesteryl esters. Cholesteryl esters, unlike cholesterol, may be absorbed from the intestinal tract into the bloodstream, and are found in cholesteryl ester laden "foam cells" contained in atherosclerotic lesions. Thus inhibition of ACAT may, by preventing cholesterol absorption from the intestinal tract into the bloodstream, help reverse, retard or prevent the atherosclerotic process. ACAT inhibition using a tryptophan ester derivative compound identified as Sandoz Compound 57-118 has been demonstrated to prevent cholesterol absorption in cholesterol fed rabbits (Heider, et al., "Role Of Acyl CoA:Cholesterol Acyltransferase In Cholesterol Absorption And Its Inhibition By 57-118 In The Rabbit", J. Lipid Res., Vol. 24, pp. 1127-34 (1983)).
Another series of experiments involving Lederle Compound CL 277,082, a trisubstituted urea compound, demonstrated that ACAT inhibition could play a role in decreasing cholesterol concentrations in plasma, liver, and aorta in rats (Schaffer, et al., "CL 277,082, A Novel Inhibitor Of Cholesterol Esterification And Cholesterol Absorption", Atherosclerosis VII, Fidge and Nestel, eds., pp. 633-36 (1986)), while a different series of experiments, involving Sandoz Compound 58-035, demonstrated that ACAT inhibition can help prevent foam cell formation in tissue culture macrophages (Tabas, et al., "Inhibition of Acyl Coenzyme A:Cholesterol Acyl Transferase in J774 Macrophages", J. Biol. Chem., Vol., 261, pp. 3147-55 (1986)). The disclosures of foregoing publications in their entireties are hereby incorporated by reference into this application in order to more fully describe the state of the art as known to those skilled therein as of the date of the invention described and claimed.
The foregoing compounds, however, are all synthetic compounds, and in animal or early human trials apparently have demonstrated undesirable side effects of toxicities.